Collaborative Research: Long-range signaling and computation in microtubules.

Currently, our ideas about biopolymers are linked to their degree of rigidity. For example, the high flexibility of DNA enables looping to regulate gene expression. By contrast, rigid microtubules, built from closely packed αβ-tubulin proteins into a hollow cylinder, are considered structural elements and highways for traffic inside cells. Recent discoveries suggest that microtubules undergo conformational changes that propagate along their length. Such changes imply that microtubules may act as responsive sensors that can send signals across the cell. Intellectual Merit: This project hypothesizes a new paradigm: that individual microtubule polymers are transmitters and amplifiers of conformational signals within a single cell, and not just structural elements. This hypothesis is tested using an interdisciplinary research plan that integrates computational modeling with experiments at the single molecule and cellular levels. Results of this project will open a new field of signaling and cellular communication via microtubules. Broader Impacts: In cell and developmental biology, mechanical signaling has mostly been considered at the extracellular and tissue scales. This project has implications that will extend these ideas to signaling along single biopolymers inside cells. In neuroscience, the results could extend mechanisms of neuronal communication to include microtubule networks in axons. In cancer biology, recent results suggest that chemotherapeutic drugs known to alter tubulin conformation may cause propagating changes, and resistant cancers have evolved to avoid this; in the long term, this work may lead to new approaches to address this resistance. In bioengineering, the observation that a handful of microtubule binders can cause long-range changes suggests that microtubules could respond to combinations of inputs and then “compute” an output by changing their structure. This could create a new subfield of biomechanical computing devices made from biopolymers. In soft/biomaterials science, our project could extend the capabilities of microtubule-based active matter by allowing conformational signaling to alter its behavior, making active materials more responsive and tunable. In addition, our project will create interdisciplinary training opportunities for undergraduate students in a team-science environment, aligned with NSF priorities to train the workforce of the future. The team will integrate mathematical modeling, single-molecule biophysics, and cell biology to determine how conformational changes are transmitted along microtubules, and how cells amplify or dampen this signaling. Aim 1 will combine computational modeling, single molecule imaging, and optical trapping to define the conformational coupling between tubulins that propagate conformational change along microtubules. Aim 2 will use computational modeling and in vitro reconstitution to examine the roles of microtubule binding proteins in creating or responding to conformational change. Aim 3 will use computational modeling and live-cell microscopy to establish the role of tubulin isotypes in creating distinct microtubules that are tuned for different levels of conformational propagation. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria. NSF Award ID: 2540467 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Radhika Subramanian | Institution: Massachusetts General Hospital, BOSTON, MA | Award Amount: $298,662 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2540467 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2540467.html